The pancreas is a glandular organ situated behind the lower stomach. Its main roles in the body include blood glucose homeostasis and the production of digestive enzymes to break down the food we eat. The pancreas produces and releases substances directly into the bloodstream (endocrine functions) and through ducts (exocrine function). The endocrine tissue of the pancreas is made up of clusters of cells called the Islets of Langherans which are responsible for producing the hormones necessary to control blood glucose. The predominant cells which make up each Islet include alpha cells, beta cells and delta cells. The beta cells are responsible for producing and secreting insulin (by the process of exocytosis) when blood glucose levels are high. Insulin acts to cause glucose uptake into surrounding muscle and adipose tissue and triggers the synthesis of fatty acids and glycogen in the liver, which reduces blood glucose and prevents prolonged hyperglycaemia. The alpha cells are responsible for secreting glucagon when blood glucose levels are below normal. Glucagon encourages the liver to synthesise glucose from glycogen stores, thus preventing hypoglycaemia. The delta cells are responsible for secreting somatostatin which acts as an inhibitor for the insulin and glucagon released, thus preventing the detrimental effects that would arise from the uncontrolled secretion of these two hormones.
FIG. 1 illustrates a typical regulation profile of insulin and glucagon. When a meal is eaten and broken down into glucose, elevation of blood glucose occurs to levels of hyperglycaemia. This stimulates insulin release that causes peripheral tissue to uptake and consume glucose. In the event of too much insulin release, glucose levels undershoot below the nominal range to hypoglycaemia. Glucagon is then released which promotes glucose release from stores in the liver, bringing blood glucose levels back to there nominal range.
Diabetes mellitus, often referred to simply as diabetes, is a condition in which the body is unable to properly produce or use insulin to process the glucose (sugar) in the blood, resulting in abnormally high blood sugar levels. There are two main types of diabetes, Type I or Type II. Type I diabetes, also known as insulin-dependent diabetes, is an auto-immune disease which results in loss of the beta cells, leading to a deficiency of insulin. This occurs mainly during childhood and current treatment is by insulin injection before meals. Furthermore, in established Type I diabetes, there is a reduced glucagon response to hypoglycaemia that is partially (or perhaps wholly) attributable to the absence of paracrine insulin action. Type II diabetes, also known as non-insulin dependant diabetes, usually occurs at an older age and is due to an insulin resistance or reduced insulin sensitivity. This causes a need for abnormally high amounts of insulin and diabetes develops when the beta cells cannot meet this demand. Treatment usually consists of a carefully managed diet and medication. However, in extreme cases injections may be required. Without monitoring and treatment diabetes can lead to hyperglycaemia, which can in turn lead to blindness, renal failure, coma and eventually death.
Current regimes for treating Type I diabetes are mainly based on injections of subcutaneous insulin several times a day, in dosages determined by intermittent blood glucose measurements. The Diabetes Control and Complications Trial (DCCT) was a major clinical study conducted by the US National Institute of Diabetes and Digestive and Kidney Diseases. The results of this trial demonstrated that intensive management using these principles could reduce complications by up to 76% (see New England Journal of Medicine, 329(14), Sep. 30, 1993). However, this reduction in hyperglycaemia related complications was at the expense of hypoglycaemia, which occurs when blood glucose drops below normal levels, especially at levels of glycosylated haemoglobin (HbA1c) below 7.5%. If not controlled, hypoglycaemia can also cause coma and eventually death. In other studies, intensive management resulted in people still spending approximately 30% of the day with glucose values of more than 10 millimole per litre (mM), and more than two hours per day in hypoglycaemia.
A possible alternative method of treating diabetes involves the use of an artificial pancreas device. Such devices could potentially bring significant improvements in the treatment of the disease and the quality of life of diabetics. Principally an artificial pancreas is closed-loop system based on the function of the beta cells for controlling hyperglycaemia, requiring a glucose sensor to determine the blood sugar levels, a control algorithm to calculate the required insulin dose and an infusion pump to deliver insulin to the blood.
Artificial pancreas control algorithms are currently either based on Proportional-Integral Derivative (PID) control or Model-based Predictive Control (MPC). PID control is a generic feedback loop mechanism which has been widely adopted in industrial systems due to its simplicity and ease of tunability. PID algorithms attempt to correct the error between a measured value of a process variable and the desired value (or setpoint) by calculating and then outputting a corrective action that can adjust the process accordingly. When used in glucose homeostasis applications, PID algorithms can continually adjust insulin infusion rates by assessing the departure of measured glucose levels from a target glucose level (the proportional component), the area-under the curve between ambient and target glucose levels (the integral component) and the change in ambient glucose level (the derivative component) (see “Closed-loop insulin delivery—the path to physiological glucose control,” Advanced Drug Delivery Reviews, vol. 56, no. 2, pp. 125-144, 2004). However, algorithms of this sort are not immune to patient variability and thus require individual tuning each time a new patient uses a device. In addition to this, the control is not pro-active, having a high associated risk of hypoglycaemia, and does not take into consideration constraints such as the bounds of hyperglycaemia and hypoglycaemia.
MPC is a control method which continually computes the optimal solution for insulin infusion for each sample of glucose taken (see “The intravenous route to blood glucose control,” IEEE Engineering in Medicine and Biology Magazine, vol. 20, no. 1, pp. 65-73, 2001). It has the ability to estimate present and future insulin delivery rates and glucose behaviour. This is significant as the control can be pro-active instead of reactive, which is an important feature for patient safety. However, these methods involve the prediction of future values that require an accurate process model, and although the models currently used do capture the glucose-insulin behaviour to some degree, they do not account for patient variability over time which can lead to significant performance degradation. Whilst several approaches have been developed to adaptively change these internal models to fit the actual patient data, these approaches tend to be complex to design, with many parameters, and require high computational power to compute an optimisation for each time step.
A recent study (see “Continuous glucose monitoring and closed-loop systems,” Diabetic Medicine, vol. 23, no. 1, pp. 1-12, 2006) has shown that patients using such artificial pancreas systems face a significant risk of experiencing hypoglycaemia. Furthermore, in the patients who did not experience hypoglycaemia, a postprandial increase in glucose of 3 mM or more was found, which kept the patient in hyperglycaemia.